**4. Discussion**

### **4.1 Comparative pharmacokinetics of antimicrobials in domestic goats**

Species variations in response to antimicrobials are very important. Various antimicrobials from different chemical classes, their routes of administration, doses, elimination half-life, bioavailability, maximal concentration, peak time, breed and spectra of activity are presented in **Table 1**. The therapeutic doses of fluoroquinolones in goats are 1.2 mg/kg subcut for levofloxacin, 5 mg/kg i.v. (orfloxacin, enrofloxacin, norfloxacin and gatifloxacin) and 20 mg/kg oral (pefloxacin). The elimination half-life (2.8 � 0.02 h) of kanamycin (5 mg/kg) and half-life (1.94 � 0.1 h) of amikacin (10 mg/kg) in Teddy and Indian native goat, respectively, show that the disposition kinetics of aminoglycosides in goats is dependent on the dose of drugs. Also, disposition kinetics of antimicrobials in goats could be species dependent. For example, Cmax (236.3 � 0.00 μg/ml) of sulfadimidine in West African dwarf (**Figure 1**) is higher than that of Pakistan female goat (6.0 � 3.0 μg/ml) and Shiba goat (2.14 � 1.05 μg/ml), respectively [16]. Tmax of West African dwarf (1.1 � 0.3 h) is lower than that of Shiba (2.0 � 1.2 h) and Netherland dwarf (2.0 � 0.5 h), respectively [18, 19]. But Vd (3.9 � 0.8 L/kg) in West African dwarf is higher than that of Nubian (0.32 � 0.0 L/kg), Shiba (0.4 � 0.2 L/kg) and cross-breed (0.3–0.5 L/kg), respectively [17, 19, 20], suggesting the difference in breed response to antimicrobials. However, half-life of kanamycin (5 mg/kg) was higher in buffaloes (4.35 � 0.24 h), cow (6.0 � 0.50 h) and sheep (3.4 � 0.1 h) than that of goat (2.8 � 0.2 h), respectively, indicating that goat is the species most sensitive to kanamycin among these species of herbivores. Also, difloxacin is effective at 5 mg/kg [8]. But normal milk reduces the activity of enrofloxacin against *E. coli* [50]. However, T1/2β (1.94 � 0.1 h) of kanamycin for normal goat is lower than the T1/2β (3.17 � 0.13 h) for febrile goat. Maintenance of therapeutic concentration (2 mg/ml) requires a priming dose of 14.73 mg/kg and

*Unique Pharmacokinetic and Pharmacodynamic Parameters of Antimicrobials in Goats DOI: http://dx.doi.org/10.5772/intechopen.84551*

maintenance dose of 13.95 mg/kg at an 8-h interval, respectively [8]. Plasma concentration of levofloxacin is higher in healthy goats (15.51 1.41 μg/ml) than mastitis goats (12.48 1.36 kg/ml). This plasma concentration does not affect levofloxacin elimination [9].

Since various brands of enrofloxacin have different pharmacokinetic parameters such as half-life (3.93 0.46; 4.04 0.53; 4.56 1.24 h) and plasma concentrations (15.53 1.31; 6.75 0.56; 10.40 2.65 μg/ml) [28], dosage formulations may have sufficient effects on pharmacokinetics and pharmacodynamics of aminoglycosides. Serum concentration of gentamicin (5 mg/kg) was maintained at 1.5–12 μg/ml for a period of 6 h. But gentamicin (2.5–3.0 mg/kg i.m.) every 8 h is therapeutically useful with less risk of nephrotoxicity [29], as daily intravenous administration of 4 mg/kg is effective for 36 h in the treatment of systemic and urinary tract infections caused by Gram-negative pathogens in goats [30]. Therefore, optimal dosage regimen, bioequivalence and kinetic parameters of antimicrobials are of clinical importance [31]. Elimination half-life, Cmax and Tmax of intramuscular enrofloxacin (2.5 mg/kg) are 5.39 0.96 h, 1.14 0.09 μg/ml and 0.83 0.13 h, respectively [51]. Gatifloxacin (5 mg/kg) provided minimum inhibitory concentration (MIC) of 0.1–2 μg/ml for susceptible microorganisms between 6 and 12 h in healthy and febrile goats, respectively [32]. Elimination half-life (3.98 0.18 h), Cmax (9.24 1.2 μg/ml), MRT (4.13 0.16 h), Vdss (1.22 0.06 L/kg) and Clb (0.24 0.01 l/h/kg) of enrofloxacin (5 mg/kg) have been reported [6]. The Vd (3.35 0.45 L/kg), Clb (0.28 0.03 l/h/kg) and T1 /2β (9.99 2.83 h) suggest long persistence of lincomycin in goat as it can be repeated every 24 h with MIC (0.6 μg/ml) for treatment of febrile bacterial infections in goats [33]. But intramuscular lincomycin can be administered every 12 h [34].

Vancomycin was initially active against methicillin-resistant *Staphylococcus*, but presently vancomycin-resistant *Staphylococcus* has emerged, and vancomycinresistant *Enterococcus* has also emerged due to its usage as feed additive. Hence, prophylactic use of antibiotics should be highly reduced [52]. Concentration of pefloxacin (0.25 μg/ml) was maintained in plasma for 6–10 h after oral or intravenous administration. Therefore, intravenous pefloxacin (20 mg/kg) every 6 h or thrice orally is effective against sensitive pathogenic microbes in goats [36]. But intravenous dose (10 mg/kg) of ciprofloxacin with T<sup>1</sup> /2β (2.72 1.04 h), MRT (3.33 1.42 h), Vdss (3.37 0.8 l/kg) and Clb (19.59 9.05 ml/min/kg), respectively, should be administered every 12 h [53]. Cefpirome (10 mg/kg) every 12 h is *useful when administered intravenously in goats. It is 19.9% plasma protein bound* [37] and so may compete weakly with other plasma-binding drugs such as sulfadimidine, warfarin, non-steroidal anti-inflammatory drugs and barbiturates. The long half-life of azithromycin after intravenous (45.2 h) and intramuscular (32.5 h) administration and MRT of 40.1 h and 60.3 h and bioavailability of 92.2% [38] show that the drug could be administered every 2 and 3 days, respectively. But half-life (67.2 h) of tulathromycin (25 mg/kg) indicates that the withdrawal period of tulathromycin may be long and there may not be a need for repeated doses of the drug. But elimination of erythromycin is higher in lactating goats (3.18 1.32 h) than non-lactating goats (1.41 1.20 h) [39] signifying that erythromycin is quickly removed from the body of non-lactating goats. MIC of erythromycin against *Staphylococcus aureus* was 0.50 and 0.75 μg/ml [54], respectively. Tylosin (10–15 mg/kg) was administered to goats both intramuscularly and intravenously. The intramuscular bioavailability was 72.6%, and serum protein binding was 37.6%, Cmax (2.38 μg/ml), Vd (1.7 L/kg), T1 /2β (3.04 h), Tmax (4.19 h) and Clb (6.8 ml/kg/min), respectively. Hence, tylosin should be injected every 14 h [43]. Gentamicin (4 mg/kg), amikacin (10 mg/kg), tobramycin (5 mg/kg), kanamycin (10 mg/kg) and apramycin (20 mg/kg) may have synergistic or additive antibacterial activity [55]. Intramuscular

Dosage rate DR ð Þ¼ bioavailability Fð Þ� dose Dð Þ

DR <sup>¼</sup> plasma concentration CP ð Þ

Infusion rate Ro ð Þ¼ plasma concentration*,*steady state Cpss ð Þ� Clb (11)

Loading dose LD ð Þ¼ target Cp � Vss

MD <sup>¼</sup> DR � DI

Bioavailability F%ð Þ¼ AUC Oral*,* Sc*,*Im � <sup>100</sup>

**4.1 Comparative pharmacokinetics of antimicrobials in domestic goats**

fluoroquinolones in goats are 1.2 mg/kg subcut for levofloxacin, 5 mg/kg i.v. (orfloxacin, enrofloxacin, norfloxacin and gatifloxacin) and 20 mg/kg oral

could be species dependent. For example, Cmax (236.3 � 0.00 μg/ml) of sulfadimidine in West African dwarf (**Figure 1**) is higher than that of Pakistan female goat (6.0 � 3.0 μg/ml) and Shiba goat (2.14 � 1.05 μg/ml), respectively [16]. Tmax of West African dwarf (1.1 � 0.3 h) is lower than that of Shiba (2.0 � 1.2 h) and Netherland dwarf (2.0 � 0.5 h), respectively [18, 19]. But Vd (3.9 � 0.8 L/kg) in West African dwarf is higher than that of Nubian (0.32 � 0.0 L/kg), Shiba (0.4 � 0.2 L/kg) and cross-breed (0.3–0.5 L/kg), respectively [17, 19, 20],

spectra of activity are presented in **Table 1**. The therapeutic doses of

Species variations in response to antimicrobials are very important. Various antimicrobials from different chemical classes, their routes of administration, doses, elimination half-life, bioavailability, maximal concentration, peak time, breed and

(pefloxacin). The elimination half-life (2.8 � 0.02 h) of kanamycin (5 mg/kg) and half-life (1.94 � 0.1 h) of amikacin (10 mg/kg) in Teddy and Indian native goat, respectively, show that the disposition kinetics of aminoglycosides in goats is dependent on the dose of drugs. Also, disposition kinetics of antimicrobials in goats

suggesting the difference in breed response to antimicrobials. However, half-life of kanamycin (5 mg/kg) was higher in buffaloes (4.35 � 0.24 h), cow (6.0 � 0.50 h) and sheep (3.4 � 0.1 h) than that of goat (2.8 � 0.2 h), respectively, indicating that goat is the species most sensitive to kanamycin among these species of herbivores. Also, difloxacin is effective at 5 mg/kg [8]. But normal milk reduces the activity of enrofloxacin against *E. coli* [50]. However, T1/2β (1.94 � 0.1 h) of kanamycin for normal goat is lower than the T1/2β (3.17 � 0.13 h) for febrile goat. Maintenance of therapeutic concentration (2 mg/ml) requires a priming dose of 14.73 mg/kg and

LD ¼ maintenance dose MD ð Þ� accumulation index Al ð Þ (15)

Rate of elimination RE ð Þ¼ CL � concentration (17)

Accumulation index <sup>¼</sup> <sup>1</sup>

*Goats (Capra) - From Ancient to Modern*

<sup>¼</sup> <sup>1</sup>

**4. Discussion**

**144**

dosage interval DI ð Þ (9)

body clearance Clb ð Þ (10)

fraction lost per dosing interval (12)

<sup>F</sup> (14)

<sup>F</sup> (16)

AUCiv (18)

<sup>1</sup> � fraction left in the body (13)

metronidazole can be administered to goats at 10 mg/kg body weight every 12 h [4]. Oxytetracycline (10 mg/kg), ampicillin (20 mg/kg) and combination of trimethoprim (20 mg/kg), sulfamethazine (50 mg/kg) and sulphamethyl phenazine (50 mg/kg) are effective in treatment of ehrlichiosis [56]. But extensive and very wide use of antimicrobial agents in goats may portend very high risk of resistance [57]. Therefore, each antimicrobial must be studied on species basis for effective and safe use for animal well-being and public safety in terms of animal product consumption and human/ animal drug resistance [3].

However, antimicrobial treatments can be monitored as follows:

*Unique Pharmacokinetic and Pharmacodynamic Parameters of Antimicrobials in Goats*

But Cpss is achieved when antimicrobial is administered repeatedly at different

However, when the body weight of goat is reduced by diarrhea or intoxicated by antimicrobials, there may be a need for fluid infusion to maximize balanced pharmacokinetic/pharmacodynamic process of antimicrobials. Clinical correlates of

Only half of calculated deficit should be administered in 1–2 h. Half replacement in 4–6 h is safer and should be completed in 2 days [65]. Isotonic solutions such as 5% dextrose and 0.9% normal saline can be administered via all routes. But hypotonic and hypertonic solutions should be administered intravenously to avoid tissue

Weighted AUC approach accounts for a more powerful PK/PD link and reveals uniqueness outcome of therapeutic indices and problems of antibiotic resistance [66]. A combination of ampicillin/sulbactam (20 mg/kg) in ratio 2:1 was administered to goat with elimination half-life of ampicillin (0.71 � 0.12 h), and sulbactam (1.02 � 0.36 h) shows that the preparation could be administered at the same dosing rate in both sheep and goats [67]. Also, intramuscular dose (2 mg/kg) of cefquinome (Cobactan 2.5%) daily yielded effective MICs against a variety of susceptible pathogenic microbes of goat including *Micrococcus luteus* [68]. Serum concentration and AUC integrated with MIC values can predict clinical success. The efficacy of macrolides, penicillins and tetracyclines is determined by the length of time, the serum concentration exceeds the MIC of a pathogenic microbe. But fluoroquinolones, aminoglycosides and metronidazole have concentration-

dependent bactericidal activity [69]. The ratio of Cmax/MIC indicates potential of antibacterial activity. Amikacin has the lowest MIC90, whereas kanamycin has the highest [55]. Co-administration of two or more drugs could also affect pharmacokinetics and pharmacodynamics of a drug. For example, West African dwarf goats are more sensitive to sulfadimidine co-administered with piroxicam (**Figure 2**) [15].

Variation is an important factor in development of antimicrobials for all species of animals including wild and domestic goats. The problems encountered are how to scale up the pharmacokinetic data from animals to human and how to extrapolate in vitro data to in vivo data for efficacy and safety [70]. There is no enough data on

**4.4 Intraspecies and interspecies scaling of antimicrobials in goats**

time of infusion min ð Þ � drop factor drops ð Þ *<sup>=</sup>*ml (25)

1

Therapeutic index TI ð Þ is defined as a ratio of Lethal dose fifty LD50 ð Þ

Effective dose ED ð Þ¼ CL � effective concentration EC ð Þ

weight loss as a measure of dehydration (>5–12%) must be considered.

Drops*=*minute <sup>¼</sup> volume of infusion ml ð Þ

Infusion rate IRð Þ¼ drug dose �

Cpss desired ð Þ � Dose previous ð Þ (22)

Effective dosefifty ED50 ð Þ (23)

Bioavailability Fð Þ (24)

drug conc � drop factor (26)

Dose new ð Þ¼ Cpss measured ð Þ

*DOI: http://dx.doi.org/10.5772/intechopen.84551*

time intervals.

reaction.

**147**

### **4.2 Pharmacokinetics of antimicrobials in wild goats**

Although the information on pharmacokinetics of wild goats is rare, allometric scaling can be applied for extrapolation of some parameters including Vd and Cl except T1/2β [58]. Ceftazidime (10 mg/kg) administered to Creole goat showed high serum concentration, good penetration and high bioavailability of the drug [45]. But cephalexin (10 mg/kg) administered (subcut, i.m. and i.v.) to *Lama glama* showed high bioavailability of 72% (i.m.) and 89% (i.v.), respectively. The MIC90 values of cephalexin against coagulase-positive staphylococci and *E. coli* were 1.0 μg/ml and 8.0 μg/ml, respectively [59]. But MIC90 value (0.01–0.1 μg/ml) of ceftazidime against *E. coli*, *Salmonella* species, *Pasteurella haemolytica* and *P. multocida* [45] shows that ceftazidime is more active and efficacious than cephalexin, which can be administered 8 mg/kg i.m. or subcut every 12 or 24 h, respectively [59]. Other modes of administration such as ballistic implants and impregnated beads can be employed for some antimicrobials to avoid frequent administration as seen in cefovecin with very long half-life in dogs and cats, allowing a dosing interval of 14 days [60, 61]. This strategy may reduce the chance of resistance by microorganisms against antimicrobials. For example, an amoxicillin formulation with half-life of 130 h can be administered every 6 days, and ceftiofur with half-life of 37 h can be administered every 2 days in goats [62]. Orbifloxacin administered to Mehsana goat (2.5 mg/kg i.v.) with T1/2β (8.63 � 0.13 h), Vdss (2.99 � 0.04 l/kg), MRT (21.07 � 0.8 h) and bioavailability (155.5%) showed antimicrobial activity against *E. faecalis*, *S. epidermidis*, *S. intermedius*, *S. aureus*, *S. pyogenes*, *E. coli*, *S. typhimurium*, *S. typhi*, *S. enterica*, *Shigella flexneri*, *K. pneumonia*, *E. aerogenes*, *P. aeruginosa*, *P. mirabilis*, *Pasteurella* species, *Mycoplasma* species and *Mannheimia haemolytica* [63].

### **4.3 Pharmacodynamics of antimicrobials**

Pharmacokinetics determine maximal therapeutic effect that depends on plasma drug concentration, drug receptors, health status and co-administration of antimicrobial with another drug that shares same or different binding receptors. Slowly eliminated and accumulated antimicrobials are least compared by poor dosing interval [64]. The maximal effect of antimicrobials is dependent on moleculereceptor interaction and drug-affinity response. Therefore,

$$\text{Drugs } (\mathbf{D}) + \text{receptor } (\mathbf{R}) \rightleftharpoons \frac{\mathbf{k\_1} \mathbf{D} \mathbf{R}}{\mathbf{k\_2}} \tag{19}$$

$$\text{Affinity constant } (\text{Kaff}) = \frac{\mathbf{k}\_1}{\mathbf{k}\_2} \tag{20}$$

$$\text{Kaff} = \frac{1}{\text{ED}\_{\text{50}}} \tag{21}$$

*Unique Pharmacokinetic and Pharmacodynamic Parameters of Antimicrobials in Goats DOI: http://dx.doi.org/10.5772/intechopen.84551*

However, antimicrobial treatments can be monitored as follows:

$$\text{Dose}(\text{new}) = \frac{\text{Cps}(\text{measured})}{\text{Cpss}(\text{desired})} \times \text{Dose}(\text{previous}) \tag{22}$$

But Cpss is achieved when antimicrobial is administered repeatedly at different time intervals.

$$\text{Therapeutic index (TI) is defined as a ratio of } \frac{\text{Lethal dose fitting (LD50)}}{\text{Effective doseitivity} (\text{ED50})} \quad \text{(23)}$$

$$\dots \qquad . \qquad \text{CL} \times \text{effective concentration (EC)}$$

$$\text{Effective dose (ED)} = \frac{\text{CL} \times \text{effective concentration (EC)}}{\text{Bioavailability (F)}} \tag{24}$$

However, when the body weight of goat is reduced by diarrhea or intoxicated by antimicrobials, there may be a need for fluid infusion to maximize balanced pharmacokinetic/pharmacodynamic process of antimicrobials. Clinical correlates of weight loss as a measure of dehydration (>5–12%) must be considered.

$$\text{Drops/minute} = \frac{\text{volume of inflation (ml)}}{\text{time of diffusion (min)}} \times \text{drop factor (drops/ml)} \tag{25}$$

$$\text{Infusion rate (IR)} = \text{drug dose} \times \frac{1}{\text{drug conc}} \times \text{drop factor} \tag{26}$$

Only half of calculated deficit should be administered in 1–2 h. Half replacement in 4–6 h is safer and should be completed in 2 days [65]. Isotonic solutions such as 5% dextrose and 0.9% normal saline can be administered via all routes. But hypotonic and hypertonic solutions should be administered intravenously to avoid tissue reaction.

Weighted AUC approach accounts for a more powerful PK/PD link and reveals uniqueness outcome of therapeutic indices and problems of antibiotic resistance [66]. A combination of ampicillin/sulbactam (20 mg/kg) in ratio 2:1 was administered to goat with elimination half-life of ampicillin (0.71 � 0.12 h), and sulbactam (1.02 � 0.36 h) shows that the preparation could be administered at the same dosing rate in both sheep and goats [67]. Also, intramuscular dose (2 mg/kg) of cefquinome (Cobactan 2.5%) daily yielded effective MICs against a variety of susceptible pathogenic microbes of goat including *Micrococcus luteus* [68]. Serum concentration and AUC integrated with MIC values can predict clinical success. The efficacy of macrolides, penicillins and tetracyclines is determined by the length of time, the serum concentration exceeds the MIC of a pathogenic microbe. But fluoroquinolones, aminoglycosides and metronidazole have concentrationdependent bactericidal activity [69]. The ratio of Cmax/MIC indicates potential of antibacterial activity. Amikacin has the lowest MIC90, whereas kanamycin has the highest [55]. Co-administration of two or more drugs could also affect pharmacokinetics and pharmacodynamics of a drug. For example, West African dwarf goats are more sensitive to sulfadimidine co-administered with piroxicam (**Figure 2**) [15].

### **4.4 Intraspecies and interspecies scaling of antimicrobials in goats**

Variation is an important factor in development of antimicrobials for all species of animals including wild and domestic goats. The problems encountered are how to scale up the pharmacokinetic data from animals to human and how to extrapolate in vitro data to in vivo data for efficacy and safety [70]. There is no enough data on

metronidazole can be administered to goats at 10 mg/kg body weight every 12 h [4]. Oxytetracycline (10 mg/kg), ampicillin (20 mg/kg) and combination of trimethoprim (20 mg/kg), sulfamethazine (50 mg/kg) and sulphamethyl phenazine (50 mg/kg) are effective in treatment of ehrlichiosis [56]. But extensive and very wide use of antimicrobial agents in goats may portend very high risk of resistance [57]. Therefore, each antimicrobial must be studied on species basis for effective and safe use for animal well-being and public safety in terms of animal product consumption and human/

Although the information on pharmacokinetics of wild goats is rare, allometric scaling can be applied for extrapolation of some parameters including Vd and Cl except T1/2β [58]. Ceftazidime (10 mg/kg) administered to Creole goat showed high serum concentration, good penetration and high bioavailability of the drug [45]. But cephalexin (10 mg/kg) administered (subcut, i.m. and i.v.) to *Lama glama* showed high bioavailability of 72% (i.m.) and 89% (i.v.), respectively. The MIC90 values of cephalexin against coagulase-positive staphylococci and *E. coli* were 1.0 μg/ml and 8.0 μg/ml, respectively [59]. But MIC90 value (0.01–0.1 μg/ml) of ceftazidime against *E. coli*, *Salmonella* species, *Pasteurella haemolytica* and *P. multocida* [45] shows that ceftazidime is more active and efficacious than cephalexin, which can be administered 8 mg/kg i.m. or subcut every 12 or 24 h, respec-

Pharmacokinetics determine maximal therapeutic effect that depends on plasma drug concentration, drug receptors, health status and co-administration of antimicrobial with another drug that shares same or different binding receptors. Slowly eliminated and accumulated antimicrobials are least compared by poor dosing interval [64]. The maximal effect of antimicrobials is dependent on molecule-

> k1DR k2

> > k2

(19)

(20)

(21)

Drugs Dð Þþ receptor Rð Þ⇄

Affinity constant Kaff ð Þ¼ k1

Kaff <sup>¼</sup> <sup>1</sup>

ED50

tively [59]. Other modes of administration such as ballistic implants and impregnated beads can be employed for some antimicrobials to avoid frequent administration as seen in cefovecin with very long half-life in dogs and cats, allowing a dosing interval of 14 days [60, 61]. This strategy may reduce the chance of resistance by microorganisms against antimicrobials. For example, an amoxicillin formulation with half-life of 130 h can be administered every 6 days, and ceftiofur with half-life of 37 h can be administered every 2 days in goats [62]. Orbifloxacin administered to Mehsana goat (2.5 mg/kg i.v.) with T1/2β (8.63 � 0.13 h), Vdss (2.99 � 0.04 l/kg), MRT (21.07 � 0.8 h) and bioavailability (155.5%) showed antimicrobial activity against *E. faecalis*, *S. epidermidis*, *S. intermedius*, *S. aureus*, *S. pyogenes*, *E. coli*, *S. typhimurium*, *S. typhi*, *S. enterica*, *Shigella flexneri*, *K. pneumonia*, *E. aerogenes*, *P. aeruginosa*, *P. mirabilis*, *Pasteurella* species, *Mycoplasma* species

animal drug resistance [3].

*Goats (Capra) - From Ancient to Modern*

and *Mannheimia haemolytica* [63].

**146**

**4.3 Pharmacodynamics of antimicrobials**

receptor interaction and drug-affinity response. Therefore,

**4.2 Pharmacokinetics of antimicrobials in wild goats**

toxicological effects of antimicrobials in goats. Hence, several extrapolations are necessary in order to arrive at safe therapeutic and toxic doses [71]. The effective therapeutic doses of some antimicrobials translated from goats to human are given in **Table 2**.

The formulas used for calculation of extrapolated doses are as follows [13, 72, 73].

$$\text{Human equivalent dose (HED)} = \frac{\text{annual dose} \times \text{annual Km}}{\text{human Km}} \tag{27}$$

$$\text{Metabolic constant (Km)} = \frac{\text{body surface area}}{\text{body weight}}\tag{28}$$

and other species of animals [78]. However, T-phage, transposon and integrin are used for resistance gene transfer. Unfortunately, the worldwide consumption of antimicrobial drugs is increasing, and the manufacturing industries are not keeping pace. The worst of it at the moment is the emergence of superbugs and super drugs. Therefore, there is a need for green antibiotics to minimize the chance of resistance [79].

*Unique Pharmacokinetic and Pharmacodynamic Parameters of Antimicrobials in Goats*

**4.7 Determination of creatinine and glomerular filtration rate as indices of**

clearance as demonstrated in the equations given below [81].

Serum creatinine Scr ð Þ¼ Ucr

in the equation given below [89].

**149**

Kidneys are responsible for water-electrolyte balance in the body, usually affected by activity-rest rhythm under hormonal influence. The diurnal changes are useful in chronobiology and chronopharmacology [80]. Many xenobiotics including antimicrobials are toxic to the kidney, and renal impairment can be assessed using creatinine clearance which is physiologically, pharmacologically and toxicologically related to body weight, clearance, volume of urine creatinine, plasma creatinine, serum creatinine, urine volume, glomerular filtration rate, creatinine clearance, creatinine half-life and depuration [81]. The plasma creatinine of Boer-Cross (0.60 mg/dl), Nubian (0.55 mg/dl) and Spanish (0.57 mg/dl) goat have been reported [82], whereas creatinine value (1.03–1.24 mg/dl) has been reported for healthy captive, Persian wild goat [83]. Area under curve could be used to determine creatinine clearance and plasma

GFR <sup>¼</sup> <sup>14616</sup>*:*<sup>8</sup>

Depuration Dep ð Þ¼ Ucr

1440

For example, paracetamol reduced glomerular filtration rate and induced less urinary excretion of isoniazid. Also, renal handling of isoniazid involved glomerular filtration, back diffusion and active tubular secretion [84]. Glomerular filtration rate which is a function of creatinine clearance can be affected by environmental and genetic factors as may be seen in native Pakistan goats administered ampicillin (20 mg/kg) with renal clearance of 0.08 ml/min/kg [85]. Hence, GFR is lower in Pakistan native than the foreign goats [86] unlike renal handling of marbofloxacin in Lohi sheep that involves both glomerular filtration and active tubular secretion [87] indicating that environment has physiological effects on various breeds of goats. This agrees with Bergmann's rule which states that light animals tend to live in hot regions of the world as opposed to fatty animals that tend to live in cold regions [88]. Since 8% of total body weight determines total blood volume, red cell volume and plasma volume could also be determined from hematocrit as indicated

Creatinine clearance CrCl ð Þ¼ Ucr

Dose Dð Þ¼ AUC � ½ � CrCl þ 25 (30)

Pcr

Pcl ¼ CrCl þ 25 (31)

CrCl ¼ Pcl–25 (32)

Crt1*=*<sup>2</sup> (33)

Pcr (34)

� 144 (36)

� 1000 1000 ml ð Þ ¼ 1 l (35)

**renal function in goats**

*DOI: http://dx.doi.org/10.5772/intechopen.84551*

But human body surface area BSA ð Þ¼ <sup>H</sup>0*:*<sup>528</sup> � <sup>W</sup>0*:*<sup>528</sup> � K (29)

whereas H = height, W = weight and K = constant.

But goat's BSA = WO.67 � <sup>10</sup>�<sup>3</sup> and dosimetric adjustment factor (DAF) is body weight of goat over body weight of humans and can be scaled up to 0.25, 0.33 and 0.58. However, body weight exponent of 0.67 and 10�<sup>3</sup> safety factor should be applied to goat, and the exponent of 0.528 should be applied to human weight and height, respectively [72, 74].

### **4.5 Antimicrobial tissue residues in goats**

Tissue residues of some antimicrobials above recommended thresholds are of public health importance. The presence of sulfadimidine residues (>0.1 ppm) in the liver, kidney, skeletal muscle, spleen, lung, brain and heart after administration of the drug (100 mg/kg) shows that the withdrawal period is longer than 30 days. Hence, sulfadimidine is not easily excreted in West African dwarf goats [13]. This may be due to the presence of desamino-sulfonamide, a sulfadimidine metabolite [75] which is eliminated slowly, thereby increasing the withdrawal time [76]. Lack of adequate water to dilute crystals of sulfadimidine in the kidney can lead to crystalluria that can consequently cause nephrosis in the affected animals [44], and consumptions of meats with high residues of sulfadimidine can cause Steven-Johnson syndrome in sensitive humans who may be slow or fast acetylators [13, 23]. Based on the tissue tolerance limit in cattle (5 ppm), the withdrawal period for tulathromycin is 19 days in cattle and 34 days in goat when administered subcutaneously [5]. The quantity of erythromycin residues (2.06 � 0.36 μg) is above the recommended threshold and may portend risk to public health. The bioavailability of tylosin in goat is 72.6� 2.3%, and its withdrawal period (48 h) [43] shows that the higher the bioavailability, the lower may be the withdrawal period in milk. Residues of antimicrobials in various tissues are presented in **Table 3**. A kid that feeds on milk with residues of antimicrobials may be vulnerable to resistance of microorganisms against the antimicrobials.

### **4.6 Antimicrobial resistance**

Goats are exposed to antimicrobials via prevention, treatment of diseases and growth promotion. This has caused the emergence of resistant *Salmonella*, *Campylobacter*, *Pasteurella*, *Actinobacillus*, *Enterococcus* and *Escherichia* species. The resistance is transferred by genes. But good and improved management practices and increased use of vaccines and probiotics could minimize emergence and spread of resistance genes [77].Off-label use of antimicrobials in goats could also contribute to emergence of resistance. Meanwhile, lack of official-generated data on consequences of extra-label use of drugs in goats cannot rule out its potential risks to goats

*Unique Pharmacokinetic and Pharmacodynamic Parameters of Antimicrobials in Goats DOI: http://dx.doi.org/10.5772/intechopen.84551*

and other species of animals [78]. However, T-phage, transposon and integrin are used for resistance gene transfer. Unfortunately, the worldwide consumption of antimicrobial drugs is increasing, and the manufacturing industries are not keeping pace. The worst of it at the moment is the emergence of superbugs and super drugs. Therefore, there is a need for green antibiotics to minimize the chance of resistance [79].
